Medial temporal lobe atrophy relates more strongly to sleep-wake rhythm fragmentation than to age or any other known risk.

Atrophy of the medial temporal lobe of the brain is key to memory function and memory complaints in old age. While age and some morbidities are major risk factors for medial temporal lobe atrophy, individual differences remain, and mechanisms are insufficiently known. The largest combined neuroimaging and whole genome study to date indicates that medial temporal lobe volume is most associated with common polymorphisms in the GRIN2B gene that encodes for the 2B subunit (NR2B) of the NMDA receptor. Because sleep disruption induces a selective loss of NR2B from hippocampal synaptic membranes in rodents, and because of several other reports on medial temporal lobe sensitivity to sleep disruption, we hypothesized a contribution of the typical age-related increase in sleep-wake rhythm fragmentation to medial temporal lobe atrophy. Magnetic resonance imaging and actigraphy in 138 aged individuals showed that individual differences in sleep-wake rhythm fragmentation accounted for more (19%) of the variance in medial temporal lobe atrophy than age did (15%), or any of a list of health and brain structural indicators. The findings suggest a role of sleep-wake rhythm fragmentation in age-related medial temporal lobe atrophy, that might in part be prevented or reversible.

How do people with dementia respond to different types of art? An explorative study into interactive museum programs.

OBJECTIVES: Various art programs are available for people with dementia. These have been shown to contribute to the patient's quality of life. But are all types of art suitable for this purpose and for the target group? This study investigated whether responsiveness during museum programs depends on the type of art work shown and/or characteristics of the person with dementia, such as severity of dementia or specific cognitive impairments. METHOD: A cross-sectional observational study was conducted in which the responsiveness of people with dementia to different types of art was investigated as part of a study into the implementation of the Unforgettable program, an interactive guided museum tour program in Dutch museums for people with dementia. RESULTS: The appreciative and active responsiveness and interaction with others during the program appeared related to the severity of dementia, to specific cognitive impairments, and to type of artworks. People with more severe dementia responded less to art than people with mild dementia. Artworks with more natural elements revealed less interaction with others. Artifacts (i.e., objects not originally meant as artworks) evoked more reactions than artworks. CONCLUSION: The study results are important to take into account when designing and offering art programs for people with dementia. Knowing which type of art works appeals most to (subgroups of) people with dementia will contribute to the optimization of art programs for this target group and to their active participation in such programs.

Tas1r3, encoding a new candidate taste receptor, is allelic to the sweet responsiveness locus Sac.

The ability to taste the sweetness of carbohydrate-rich foodstuffs has a critical role in the nutritional status of humans. Although several components of bitter transduction pathways have been identified, the receptors and other sweet transduction elements remain unknown. The Sac locus in mouse, mapped to the distal end of chromosome 4 (refs. 7-9), is the major determinant of differences between sweet-sensitive and -insensitive strains of mice in their responsiveness to saccharin, sucrose and other sweeteners. To identify the human Sac locus, we searched for candidate genes within a region of approximately one million base pairs of the sequenced human genome syntenous to the region of Sac in mouse. From this search, we identified a likely candidate: T1R3, a previously unknown G protein-coupled receptor (GPCR) and the only GPCR in this region. Mouse Tas1r3 (encoding T1r3) maps to within 20,000 bp of the marker closest to Sac (ref. 9) and, like human TAS1R3, is expressed selectively in taste receptor cells. By comparing the sequence of Tas1r3 from several independently derived strains of mice, we identified a specific polymorphism that assorts between taster and non-taster strains. According to models of its structure, T1r3 from non-tasters is predicted to have an extra amino-terminal glycosylation site that, if used, would interfere with dimerization.

Visual hallucinations in Parkinson's disease are associated with thinning of the inner retina.

Visual hallucinations (VH) are common in patients with Parkinson's disease (PD), yet the underlying pathophysiological mechanisms are still unclear. We aimed to explore the association of the presence of VH with inner retinal thinning and, secondarily, with visual acuity. To this end, we included 40 PD patients in this exploratory study, of whom 14 had VH, and 22 age- and sex-matched healthy controls. All participants were interviewed for the presence of VH by a neurologist specialized in movement disorders and underwent a thorough ophthalmologic examination, including measurement of the best-corrected visual acuity (BCVA) and optical coherence tomography to obtain macular scans of the combined ganglion cell layer and inner plexiform layer (GCL-IPL). Patients with VH had a thinner GCL-IPL than patients without VH, which persisted after correction for age, disease stage, levodopa equivalent daily dose (LED) and cognitive function. Furthermore, BCVA was lower in the PD group with VH than in the PD group without VH, although only a trend remained after correction for age, disease stage, LED and cognitive function. Taken together, in patients with PD, visual hallucinations appear to be associated with a thinning of the inner retinal layers and, possibly, with reduced visual acuity. Further research using a longitudinal design is necessary to confirm these findings and to establish the causality of these relationships.

Cognitive functioning in patients with carotid artery occlusion; a systematic review.

INTRODUCTION: Patients with complete occlusion of the internal carotid artery (CAO) are vulnerable to cerebral hypoperfusion. Since cerebral hypoperfusion is associated with accelerated cognitive decline, patients with CAO may have an increased risk of cognitive impairment. We aimed to assess the prevalence and profile of cognitive impairment in patients with CAO and to explore the relation between hemodynamic impairment and cognitive functioning. METHODS: We systematically searched Medline and EMBASE for studies including patients with symptomatic or asymptomatic CAO subjected to cognitive testing that were published between 1980 and 2017. We did not include patients with carotid stenosis. We obtained data on type of study, patient characteristics, cerebral imaging and neuropsychological testing. In addition, we extracted data on potential causes of systemic hemodynamic impairment and the presence and stage of cerebral hemodynamic impairment. We assessed methodological quality of included studies with the Newcastle-Ottawa Scale. RESULTS: We found eight studies comprising 244 patients (mean age 61 years, 76% male, 93% symptomatic CAO). The proportion of patients with cognitive impairment ranged from 54 to 71% in four studies; in the other four studies patients with CAO performed worse on cognitive testing than controls, but results were not quantified. Impairment was reported in all cognitive domains. We found no data on the association between systemic hemodynamic impairment and cognitive functioning. Studies that assessed whether cerebral hemodynamic impairment was associated with cognitive functioning showed conflicting results. CONCLUSION: In patients with CAO, cognitive impairment is present in about half to two-thirds of patients and is not restricted to specific cognitive domains. The effect of systemic and cerebral hemodynamic impairment on cognitive functioning in patients with CAO deserves further study.

Characterization of novel cathepsin K mutations in the pro and mature polypeptide regions causing pycnodysostosis.

Cathepsin K, a lysosomal cysteine protease critical for bone remodeling by osteoclasts, was recently identified as the deficient enzyme causing pycnodysostosis, an autosomal recessive osteosclerotic skeletal dysplasia. To investigate the nature of molecular lesions causing this disease, mutations in the cathepsin K gene from eight families were determined, identifying seven novel mutations (K52X, G79E, Q190X, Y212C, A277E, A277V, and R312G). Expression of the first pro region missense mutation in a cysteine protease, G79E, in Pichia pastoris resulted in an unstable precursor protein, consistent with misfolding of the proenzyme. Expression of five mature region missense defects revealed that G146R, A277E, A277V, and R312G precursors were unstable, and no mature proteins or protease activity were detected. The Y212C precursor was activated to its mature form in a manner similar to that of the wild-type cathepsin K. The mature Y212C enzyme retained its dipeptide substrate specificity and gelatinolytic activity, but it had markedly decreased activity toward type I collagen and a cathepsin K-specific tripeptide substrate, indicating that it was unable to bind collagen triple helix. These studies demonstrated the molecular heterogeneity of mutations causing pycnodysostosis, indicated that pro region conformation directs proper folding of the proenzyme, and suggested that the cathepsin K active site contains a critical collagen-binding domain.

Human rights and mass disaster: lessons from the 2004 tsunami.

This paper describes the results of an investigation into how the December, 2004 tsunami and its aftermath affected the human rights of the survivors. Teams of researchers interviewed survivors, government officials, representatives of international and local nongovernmental organisations, UN officials, the military, police, and other key informants in India, Sri Lanka, the Maldives, Indonesia, and Thailand. We also analysed newspaper articles, reports released by governments, UN agencies, NGOs, and private humanitarian aid groups, and we examined the laws and policies related to survivors' welfare in the affected countries. We found worsening of prior human rights violations, inequities in aid distribution, lack of accountability and impunity, poor coordination of aid, lack of community participation in reconstruction, including coastal redevelopment. Corruption and preexisting conflict negatively impact humanitarian interventions. We make recommendations to international agencies, states, and local health service providers. A human rights framework offers significant protection to survivors and should play a critical role in disaster response.

Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): a review of four consecutive childhood AML trials conducted between 1981 and 2000.

From 1981 to 2000, a total of 1823 children with acute myeloid leukemia (AML) enrolled on four consecutive Pediatric Oncology Group (POG) clinical trials. POG 8101 demonstrated that the induction rate associated with the 3+7+7 combination of daunorubicin, Ara-C, and 6-thioguanine (DAT) was greater than that associated with an induction regimen used to treat acute lymphoblastic leukemia (82 vs 61%; P=0.02). Designed as a pilot study to determine the feasibility of administration of noncross-resistant drug pairs and later modified to assess the effect of dose intensification of Ara-C during the second induction course, POG 8498 confirmed the high initial rate of response to DAT (84.2%) and showed that dose intensification of Ara-C during the second induction course resulted in a trend toward higher event-free survival (EFS) estimates than did standard-dose DAT (2+5) during the second induction course (5 year EFS estimates, 22 vs 27%; P=0.33). Age <2 years and leukocyte count <100 000/mm3 emerged as significantly good prognostic factors. The most significant observation made in the POG 8498 study was the markedly superior outcome of children with Down's syndrome who were treated on the high-dose Ara-C regimen. POG 8821 compared the efficacy of autologous bone marrow transplantation (BMT) with that of intensive consolidation chemotherapy. Intent-to-treat analysis revealed similar 5-year EFS estimates for the group that underwent autologous BMT (36+/-4.7%) and for the group that received only intensive chemotherapy (35+/-4.5%) (P=0.25). There was a high rate of treatment-related mortality in the autologous transplantation group. The study demonstrated superior results of allogeneic BMT for patients with histocompatible related donors (5-year EFS estimate 63+/-5.4%) and of children with Down's syndrome (5-year EFS estimate, 66+/-8.6%). The POG 9421 AML study evaluated high-dose Ara-C as part of the first induction course and the use of the multidrug resistance modulator cyclosporine. Preliminary results showed that patients receiving both high-dose Ara-C for remission induction and the MDR modulator for consolidation had a superior outcome (5-year EFS estimate, 42+/-8.2%) than did patients receiving other treatment; however, the difference was not statistically significant. These four studies demonstrate the importance of dose intensification of Ara-C in the treatment of childhood AML; cytogenetics as the single most prognostic factor and the unique curability of AML in children with Down's syndrome.

Studies on histamine H2 receptors coupled to cardiac adenylate cyclase. Effects of guanylnucleotides and structural requirements for agonist activity.

In particulate preparations from guinea-pig ventricle, histamine in the concentration range 10(-6)--10(-3) M caused a 3--5fold stimulation of adenylate cyclase activity which was dependent on the presence of GTP. The effects of fourteen analogs of histamine were examined on this cyclase preparation. Five of the compounds studied proved to be partial agonists relative to histamine while nine others had essentially the same intrinsic activity as histamine. The intrinsic activities of the partial agonists were increased by GppNHp to the extent that dimaprit, which was a partial agonist in the presence of GTP, became a full agonist in the presence of GppNHp. The relative potencies of the full agonists as activators of the cyclase were found to correlate with the relative potencies on physiologically defined H2 receptor systems. Activation of the cyclase by histamine, as well as by several of the agonist analogs, including dimaprit and tolazoline, was completely blocked by the H2 antagonist cimetidine, but was not affected by pharmacologically relevant concentrations of the H1 antagonist mepyramine, the beta-blocker alprenolol, or the alpha-blocker phentolamine. The results suggest that all the agonists studied probably interact with a common H2 receptor site on the cardiac muscle cell leading to activation of adenylate cyclase. The accompanying increase in cyclic AMP is presumably responsible for the chronotropic and inotropic effects of histamine and related compounds on cardiac muscle.

An anti-A1 lectin in the seeds of Amphicarpaea bracteata.

An anti-A1 lectin has been isolated from the extract of Amphicarpaea bracteata seeds by affinity chromatography on Epoxy-activated Sepharose 6B coupled to N-acetyl-D-galactosamine. The yield of the purified lectin was 86 microgram/g of seeds. The purified lectin shows one main band on electrophoresis in sodium dodecyl sulfate-polyacrylamide. The amino acid and neutral sugar composition indicate that this lectin is an acidic glycoprotein with a neutral sugar content of approx. 2%. The composition of the lectin is different from that of the Dolichos biflorus lectin but the two lectins have some common characteristics. The most powerful inhibitors of the agglutination of A1 red blood cells by the A. bracteata lectin is N-acetyl-D-galactosamine. Much weaker inhibitors of the agglutination are alpha-lactose, D-fucose, and five other sugars.

Keratan sulfate-like glycosaminoglycan in the cerebral cortex of the brain and its variation with age.

A keratan sulfate-like substance was found kn the cerebral cortex proteoglycans of rats. This substance tripled during the rapid growth phase from 1 to 3 months of age and then decreased steadily to a negligible quantity in the senescent rat, aged 25 months. In contrast, the uronic acid-containing glycosaminoglycans remained constant during the life span studied. The marked decrease observed in the proportion of keratan sulfate-like moiety to the other glycosaminoglycans in the cerebral cortex of the senescent rat (aged 25 months) compared with the young adult rat (aged 3 months) may explain the reduced extracellular volume observed by others in the senescent brain.

Long-term results of the APO protocol (vincristine, doxorubicin [adriamycin], and prednisone) for treatment of mediastinal lymphoblastic lymphoma.

Twenty-one patients with biopsy-proven mediastinal lymphoblastic lymphoma were treated with the APO protocol (vincristine, doxorubicin, and prednisone). Treatment consisted of two years of therapy with a modified doxorubicin-containing acute lymphoblastic leukemia regimen with preventive cranial irradiation and intrathecal methotrexate. The median age in the group was 13 years (range, 2.5-22 years). Complete remission was obtained in 20 of 21 patients. Three patients required mediastinal irradiation for successful remission induction. Six patients have subsequently relapsed: two in the central nervous system, one in the central nervous system and testicle, one in the testicle, one in the pleura, and one in the abdomen. The median follow-up is six years (range, 16 months to 9.5 years) and a Kaplan-Meier estimate of disease-free survival at three years is 58% +/- 23% (2 SE).

HiC-COM: a 2-month intensive chemotherapy regimen for children with stage III and IV Burkitt's lymphoma and B-cell acute lymphoblastic leukemia.

We designed a protocol that included 2 months of intensive Cytoxan (cyclophosphamide; Bristol-Myers Co, Evansville, IN), high-dose methotrexate (MTX), high-dose cytarabine (ara-C), and vincristine (HiC-COM) to improve event-free survival (EFS) for patients with advanced-stage Burkitt's lymphoma and B-cell acute lymphoblastic leukemia (ALL). We also wished to test the feasibility of rapidly cycling Cytoxan and high-dose ara-C based on signs of early marrow recovery. Twenty patients including 12 with stage III Burkitt's lymphoma and eight with stage IV Burkitt's lymphoma or B-cell ALL were entered onto this pilot study. The rate of complete remission was 95%. Four patients have relapsed. The 2-year actuarial EFS was 75% (median follow-up, 37 months). Two of the initial five patients developed transverse myelitis, which we believe may have been secondary to the concomitant administration of intrathecal (IT) and high-dose systemic ara-C. We conclude that this short but intensive regimen is highly effective for patients with advanced Burkitt's lymphoma and B-cell ALL. EFS has improved over previous less intensive regimens, and is comparable to regimens of longer duration.

Wide-field radiation therapy alone or with chemotherapy for Hodgkin's disease in relapse from combination chemotherapy.

Nineteen patients with Hodgkin's disease who relapsed primarily in nodal sites after intensive combination chemotherapy were retreated with wide-field radiation therapy alone or with additional chemotherapy between January 1971 and December 1984. Six patients presented in second relapse and 13 patients in first relapse. Seven patients were treated with combination chemotherapy and radiation therapy and twelve patients were treated with radiation therapy alone. Radiation therapy field sizes and doses were similar to those recommended for early-stage Hodgkin's disease patients treated with radiation therapy alone. The 5-year actuarial freedom from relapse (FFR) and survival following retreatment were 48% and 69%, respectively. Twelve patients are currently disease-free 12 to 172 months following retreatment. Wide-field radiation therapy alone or with additional chemotherapy should be considered for patients with advanced Hodgkin's disease who relapse in nodal sites after initial combination chemotherapy.

Unusual thoracic radiographic findings in children treated for Hodgkin's disease.

Mantle irradiation is often part of the treatment for Hodgkin's disease. Localized pneumonitis and fibrosis are well-known sequelae of this treatment. We report nine patients with unusual thoracic radiographic findings following treatment for Hodgkin's disease. All nine had mediastinal widening. Seven of these patients received combined modality therapy in which prednisone was given with their MOPP. In these seven patients, an increase in mediastinal width developed at the same time as the radiographic changes of radiation pneumonitis. Two patients developed bilateral infiltrates extending beyond the field of radiation to the lung periphery. In one of these patients, a spontaneous pneumomediastinum developed. One patient underwent mediastinal biopsy that revealed inflammatory changes similar to those seen in radiation pneumonitis. All patients either responded to steroids or had spontaneous regression of radiographic abnormalities supporting the presumed diagnosis of treatment related changes. Recognition of these unusual sequelae of mantle irradiation will aid in differentiating them from infection or tumor and lead to prompt, appropriate treatment.

Therapy of refractory or recurrent childhood acute myeloid leukemia using amsacrine and etoposide with or without azacitidine: a Pediatric Oncology Group randomized phase II study.

PURPOSE: A randomized study compared the combination of amsacrine (100 mg/m2/d on days 1 to 5) and etoposide (200 mg/m2/d on days 1 to 3) with the same two agents plus azacitidine (250 mg/m2/d on days 4 to 50) for the therapy of induction-resistant or relapse childhood acute myeloid leukemia (AML). PATIENTS AND METHODS: One hundred sixty-seven assessable children with AML who either had failed to respond to primary induction therapy (group 1, n = 41) or had relapsed (group 2, n = 126) were randomized. RESULTS: Overall, there were 56 complete responses (34%; SE 4%). Among primary refractory patients (group 1), the complete response rate was higher with the three-drug regimen (18% vs 53%, P = .03). In the relapsed patients (group 2), there was no difference in complete response rates related to treatment (31% vs 35%, P = .3). There were 17 early deaths. The major toxicities for both regimens were myelosuppression and infection. CONCLUSION: The overall complete response rate of 34% in this patient population is indicative of effective antileukemic activity. For patients with relapsed leukemia, the addition of azacitidine to etoposide and amsacrine did not improve response. The suggested advantage of the three-drug regimen for induction failures warrants further investigation.

Emergency prebiopsy radiation for mediastinal masses: impact on subsequent pathologic diagnosis and outcome.

From 1968 to 1983, 19 patients were treated at the Joint Center for Radiation Therapy for symptomatic mediastinal masses before a biopsy was obtained. This study evaluates the impact of radiation on the ability to establish a pathologic diagnosis and the results of subsequent empirical therapy if no diagnosis was established. Eight of the 19 (42%) patients were not able to have a histologic diagnosis established at the time of biopsy. Seven of these eight patients went on to receive empiric therapy for what was thought to be the most likely diagnosis on clinical grounds. Four of the seven have not relapsed; three who have relapsed were found to have the diagnosis for which they were empirically treated. The untreated patient relapsed with seminoma. Thus, the use of emergency irradiation for mediastinal masses is sometimes associated with the loss of pathologic diagnosis. These patients likely have a radioresponsive disease (ie, lymphoma or seminoma) that may be treated successfully on the presumed clinical diagnosis even when the histologic diagnosis is lost secondary to prebiopsy irradiation.

Primary lymphoma of bone in children: analysis of treatment results with adriamycin, prednisone, Oncovin (APO), and local radiation therapy.

Primary lymphoma of bone is an unusual extranodal presentation of pediatric non-Hodgkin's lymphoma (NHL). Treatment with radiotherapy alone has resulted in a disease-free survival rate of approximately 50% in most adult series. Between January 1973 and April 1985, 11 children with biopsy-proven NHL of bone were seen and treated at our institutions. The minimal clinical staging included chest and bone radiographs, a radionuclide bone scan, complete blood cell counts and serum chemistries, and a bone marrow aspirate and biopsy. The age range was 9 to 17 years with a median age of 14 years. Histology included diffuse lymphoblastic lymphoma in four patients and diffuse histiocytic lymphoma in seven. Each patient was treated with the Adriamycin/prednisone/Oncovin (APO) protocol and ten patients received concomitant radiation to the whole bone when possible and a boost to the primary lesion(s). The median tumor dose was 5,000 rad (range, 3,600 to 5,600). The median follow-up was 8 years. There have been no relapses, but two patients have developed second bone tumors 5 and 7 1/2 years after beginning therapy. Each second tumor arose directly in the radiation field. The overall 8-year actuarial survival is 83%. We conclude that APO and local radiation results in excellent overall survival for children with primary NHL of bone. The occurrence of two second bone tumors, however, raises questions regarding dose and/or the role of radiation for this disease.

Bone marrow transplantation for myelodysplasia and secondary acute nonlymphoblastic leukemia.

Twenty-three patients with primary myelodysplasia (MDS) or secondary myelodysplasia/acute nonlymphocytic leukemia (MDS/ANLL) were treated with allogeneic or syngeneic bone marrow transplantation (BMT). Only one patient was in a chemotherapy-induced hematologic remission. Graft-versus-host disease prophylaxis included methotrexate, methotrexate plus cyclosporine, cyclosporine, or T-cell depletion using one of two anti-CD5 monoclonal antibodies. For patients with primary MDS, the median age was 19 years (range, 11 to 41 years) and the actuarial disease-free survival was 56% +/- 21% (median follow-up, 2 years; range, 0.8 to 5 years). There were three graft failures (two with autologous recovery) and two early deaths. Outcome appeared to be related to French-American-British (FAB) classification. For patients with secondary MDS/ANLL, the median age was 28 years (range, 3 to 16 years) and the actuarial disease-free survival was 27% +/- 13% (median follow-up, 5 years; range, 2.5 to 8.5 years). There were no graft failures, two relapses, and four early deaths. The presence of marrow fibrosis per se did not predict for graft failure (P = .21); however, the use of T-cell depleted marrow in patients with marrow fibrosis resulted in graft failure in three of five individuals. Our results suggest that in patients with primary MDS or secondary MDS/ANLL, BMT should be considered early in the course of the disease, and that attempts at inducing a remission prior to BMT appeared to be unnecessary. In MDS patients with marrow fibrosis, T-cell depletion should be avoided.

Stage IA-IIB Hodgkin's disease: staging and treatment of patients with large mediastinal adenopathy.

Ninety-two patients with clinically staged (CS) IA-IIB Hodgkin's disease (HD) with large mediastinal adenopathy (LMA) underwent three different staging and treatment approaches between April 1969 and December 1984. These approaches included: (1) staging laparotomy followed by radiation therapy (RT) alone; (2) staging laparotomy followed by combined RT and chemotherapy (CMT); or (3) clinical staging followed by CMT. Patients treated with CMT were more likely to have "B" symptoms, extension into extranodal sites, or stage III disease. Patients treated with RT alone had a significantly higher risk of relapse as compared to patients receiving CMT. No overall survival differences were seen between the three groups of patients. For patients treated with CMT without RT to the spleen or abdominal nodes, the risk of relapse in the abdomen was low (4%). These data suggest that for those CS I-II HD patients with LMA who are treated with CMT, the role for staging laparotomy and abdominal irradiation is limited. RT alone remains an option for some patients with LMA, but careful assessment of the anatomic extent of thoracic disease as well as staging laparotomy is essential if such treatment is recommended.